Neurotrophins are a family of small, homodimeric proteins, which play a crucial role in the development and maintenance of the nervous system. Members of the neurotrophin family include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5), neurotrophin-6 (NT-6), and neurotrophin-7 (NT-7). Neurotrophins, similar to other polypeptide growth factors, affect their target cells through interactions with cell surface receptors. According to current knowledge, two kinds of transmembrane glycoproteins serve as receptors for neurotrophins. Neurotrophin-responsive neurons possess a common low molecular weight (65-80 kDa), low affinity receptor (LNGFR), also termed as p75NTR or p75, which binds NGF, BDNF, NT-3 and NT-4/5 with a KD of 2×10−9 M; and large molecular weight (130-150 kDa), high-affinity (KD in the 10−11 M range) receptors, which are members of the trk family of receptor tyrosine kinases. The identified members of the trk receptor family are trkA, trkB, and trkC.
TrkC is widely expressed in the central nervous system, and on a subset of neurons in the peripheral nervous system. TrkC is also expressed on some parasympathetic, enteric neurons, and some non-neural tissues. It is expressed on sympathetic neurons and on a subset of primary sensory neurons of the DRG, the large fiber sensory neurons of the DRG. Large fiber sensory neurons have large myelinated axons extending to the periphery, where they convey information regarding proprioception, and fine touch and vibration sense.
The extracellular domains of full-length native trkA, trkB and trkC receptors have five structural domains that have been defined with reference to homologous or otherwise similar structures identified in various other proteins. The domains have been designated starting at the N-terminus of the amino acid sequence of the mature trk receptors as 1) a first cysteine-rich domain; 2) a leucine-rich domain; 3) a second cysteine-rich domain; 4) a first immunoglobulin-like domain; and 5) a second immunoglobulin-like domain. See, e.g., PCT Publication No. WO 0198361; Urfer et al. J. Biol. Chem. 273: 5829-5840 (1998).
Neurotrophins are of interest as potential therapeutic agents for a variety of neurodegenerative and neurological diseases. Neurotrophins, such as NGF and NT-3, were tested in animal models for treating sensory neuropathy associated with pyridoxine or cis-platinum treatment. U.S. Pat. No. 5,604,202; PCT Publication No. WO 0198361. Using neurotrophins in treatment of neurodegenerative and neurological diseases have several shortcomings. One significant shortcoming is the lack of specificity. Most neurotrophins cross-react with more than one receptor. For example NT-3, the preferred ligand of the trkC receptor tyrosine kinase, also binds to and activates trkA and trkB (Barbacid, J. Neurobiol. 25:1386-1403, 1994; Barbarcid, Ann. New York Aced. Sci. 766:442-458, 1995; Ryden and Ibanez, J. Biol. Chem. 271:5623-5627, 1996, Belliveau et al., J. Cell. Biol. 136:375-388, 1997; Farinas et al., Neuron 21:325-334, 1998). As a result, it is difficult to devise therapies that target a specific population of neurons. Another limitation of neurotrophin therapy is that neurotrophins, including NT-3, are known to elicit hyperalgesia (Chaudhry et al., Muscle and Nerve 23:189-192, 2000). In addition, some neurotrophins such as NT-3 have poor pharmacokinetic and bioavailability properties in rodents, which raise serious questions about their human clinical applications (Haase et al., J. Neurol. Sci. 160:S97-S105, 1998, dosages used in Helgren et al., J. Neurosci. 17(I):372-82, 1997). There is therefore a need for the development of new therapeutic agents for the treatment of neurodegenerative disorders and neurological diseases that are devoid of the known shortcoming of neurotrophins.
Rodent agonist anti-trkC antibodies have been reported. See PCT Publication No. WO 01/98361. However, when rodent antibodies are used therapeutically in humans, a human anti-murine antibody response develops in significant numbers of treated individuals. In addition, effector functions of mouse antibodies have proven to be less efficient in the human context. Thus, there is a serious need for improved agonist anti-trkC antibodies, including humanized agonist anti-trkC agonist antibodies.
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